The long-term objective is to elucidate the mechanisms of carcinogenesis by nickel compounds. The current specific aims are: (1) to test and to rank the carcinogenic activities of selected nickel compounds that occur in the human environment and workplace, by administration to Fischer rats via intramuscular (im), intrarenal (ir), and oral routes, (2) to evaluate correlations between the carcinogenic activities of these nickel compounds and their (a) dissolution rates in biological media, (b) rates of complexation with glutathione, (c) susceptibilities to phagocytosis by rat macrophages, (d) induction of erythrocytosis after ir injection in rats, and (e) stimulation of heme oxygenase activity in rat kidney microsomes; (3) to elucidate the pathogenesis and interrelationships of three phenomena that develop in rats after ir injection of Ni3S2: (a) mesangial hyperplasia in renal glomeruli, (b) increased renal production of erythropoietin, and (c) development of renal cancers; (4) to determine the subcellular distribution and macromolecular binding of 63Ni in renal homogenates after ir implantation of 63Ni3S2 within semipermeable tubules; (5) to explore the effects of nickel compounds upon gene expression; (6) to establish the molecular basis for the inhibitory effect of manganese upon Ni3S2-carcinogenesis, and (7) to develop new experimental models for study of nickel carcinogenesis. The test materials include nickel sulfides, selenides, arsenides, oxides, antimonide, titanate, chloride, sulfate, and acetate. The methods include: (1) carcinogenesis testing in rats, (2) histological and ultrastructural examinations of rat tissues, (3) erythropoietin bioassays of rat serum and kidney homogenates, (4) chromatographic, electrophoretic, and ultracentrifugal fractionations of 63Ni-bound to macromolecules, with detection of 63Ni by autoradiography and scintillation counting, and (5) gas chromatographic assays of heme oxygenase activity. The scientific disciplines are pathology and toxicology. Health relatedness: This study furnishes basic knowledge about nickel carcinogenesis and provides information with practical applications to human hazards of carcinogenesis from nickel compounds, with particular relevance to occupational exposures and environmental pollution from nickel refining, coal gasifications, oil shale retorting, and Ni-plating.